Loss of a key regulatory molecule, A20, in immune sentinel cells is sufficient to trigger colitis and colitis-associated arthritic disease according to a report published this week in Nature Immunology.

A20 suppresses inflammation by turning off multiple signaling pathways that activate the transcription factor NF-kappaB, which is needed to turn on the genes encoding inflammatory mediators. Mice lacking A20 die prenatally, pointing to its important role. Ma and colleagues generated mice that lack A20 only in dendritic cells, which activate adaptive immune cells upon infection or immunization. Uninfected A20 mice have increased numbers of activated T cells and spontaneously develop overt autoinflammatory disease, but were largely devoid of autoantibodies and antibody-triggered immunopathologies.

The disease spectrum observed in the A20-deficient mice is reminiscent of that seen in human patients with colitis and other antibody-independent arthritic diseases. Genomic analyses on a cohort of Crohn’s patients likewise identified disease-linked point mutations in the human A20 gene. These data suggest altered expression of A20 can predispose individuals to autoinflammatory diseases.